1. Field of the Invention
The present invention relates to the fields of retinoid receptor biology and mammalian disease therapeutics. Specifically, the present invention provides compositions and methods for treating an animal, preferably a human, suffering from or predisposed to a physical disorder, by administering to the animal an effective amount of a composition comprising at least one RAR antagonist, preferably an RARxcex1 antagonist, and at least one RXR agonist.
2. Related Art
Retinoids
A number of studies have demonstrated that retinoids (vitamin A derivatives) are essential for normal growth, vision, tissue homeostasis, reproduction and overall survival (for reviews and references, See Spom et al., The Retinoids, Vols. 1 and 2, Sporn et al., eds., Academic Press, Orlando, Fla. (1984)). For example, retinoids have been shown to be vital to the maintenance of skin homeostasis and barrier function in mammals (Fisher, G. J., and Voorhees, J. J., FASEB J. 10:1002-1013 (1996)). Retinoids are also apparently crucial during embryogenesis, since offspring of dams with vitamin A deficiency (VAD) exhibit a number of developmental defects (Wilson, J. G., et al., Am. J. Anat. 92:189-217 (1953); Morriss-Kay, G. M., and Sokolova, N., FASEB J. 10:961-968 (1996)). With the exceptions of those on vision (Wald, G., et al., Science 162:230-239 (1968)) and spernatogenesis in mammals (van Pelt, H. M. M., and De Rooij, D. G., Endocrinology 128:697-704 (1991)), most of the effects generated by VAD in animals and their fetuses can be prevented and/or reversed by retinoic acid (RA) administration (Wilson, J. G., et al., Am. J. Anat. 92:189-217 (1953); Thompson etal., Proc. Royal Soc. 159:510-535 (1964); Morriss-Kay, G. M., and Sokolova, N., FASEB J. 10:961-968 (1996)). The dramatic teratogenic effects of maternal RA administration on mammalian embryos (Shenefelt, R. E., Teratology 5, 103-108 (1972); Kessel, M., Development 115:487-501 (1992); Creech Kraft, J., In Retinoids in Normal Development and Teratogenesis, G. M. Morriss-Kay, ed., Oxford University Press, Oxford, UK, pp. 267-280 (1992)), and the marked effects of topical administration of retinoids on embryonic development of vertebrates and limb regeneration in amphibians (Mohanty-Hejmadi et al., Nature 355:352-353 (1992); Tabin, C. J., Cell 66:199-217 (1991)), have contributed to the notion that RA may have critical roles in morphogenesis and organogenesis.
Retinoid Receptors
Except for those involved in visual perception (Wald, G. et al., Science 162:230-239 (1968)), the molecular mechanisms underlying the highly diverse effects of retinoids have until recently remained obscure. The discovery of nuclear receptors for RA (Petkovich et al., Nature 330:444-450 (1987); Giguxc3xa8re et al., Nature 330:624-629 (1987)) has greatly advanced the understanding of how the retinoids may exert their pleiotropic effects (Leid et al., TIBS 17:427-433 (1992); Linney, E., Current Topics in Dev. Biol. 27:309-350 (1992)). Since this discovery it has become apparent that the genetic activities of the RA signal are mediated through two families of receptorsxe2x80x94the RAR family and the RXR familyxe2x80x94which belong to the superfamily of ligand-inducible transcriptional regulatory factors that include steroid/thyroid hormone and vitamnin D3 receptors (for reviews see Leid et al., TIBS 17:427-433 (1992); Chambon, P., Semin. Cell Biol. 5:115-125 (1994); Chambon, P., FASEB J. 10:940-954 (1996); Giguere, V., Endocrinol. Rev. 15:61-79 (1994); Mangelsdorf, D. J., and Evans, R. M., Cell 83:841-850 (1995); Gronemeyer, H., and Laudet, V., Protein Profile 2:1173-1236 (1995)).
RAR Receptors
Receptors belonging to the RAR family (RARxcex1, xcex2 and xcex3 and their isoforms) are activated by both all-trans- and 9-cis-RA (Leid et al., TIBS 17:427-433 (1992); Chambon, P., Semin. Cell Biol. 5:115-125 (1994); Dollxc3xa9, P., et al., Mech. Dev. 45:91-104 (1994); Chambon, P., FASEB J. 10:940-954 (1996)). Within a given species, the DNA binding (C) and the ligand binding (E) domains of the three RAR types are highly similar, whereas the C-terminal domain F and the middle domain D exhibit no or little similarity. The amino acid sequences of the three RAR types are also notably different in their B regions, and their main isoforms (xcex11 and xcex12, xcex21 to xcex21xcex24, and xcex31 and xcex32) further differ in their N-terminal A regions (Leid et al., TIBS 17:427-433 (1992)). Amino acid sequence comparisons have revealed that the interspecies conservation of a given RAR type is greater than the similarity found between the three RAR types within a given species (Leid et al., TIBS 17:427-433 (1992)). This interspecies conservation is particularly striking in the N-terminal A regions of the various RARxcex1, xcex2 and xcex3 isoforms, whose A region amino acid sequences are quite divergent. Taken together with the distinct spatio-temporal expression patterns observed for the transcripts of each RAR and RXR type in the developing embryo and in various adult mouse tissues (Zelent, A., et al., Nature 339:714-717 (1989); Dollxc3xa9, P., et al., Nature 342:702-705 (1989); Dollxc3xa9 et al., Development 110:1133-1151 (1990); Ruberte et al., Development 108:213-222 (1990); Ruberte et al., Development 111:45-60 (1991), Mangelsdorf et al., Genes and Dev. 6:329-344 (1992)), this interspecies conservation has suggested that each RAR type (and isoform) may perform unique functions. This hypothesis is further supported by the finding that the various RAR isoforms contain two transcriptional activation functions (AFs) located in the N-terminal A/B region (AF-1) and in the C-terminal E region (AF-2), which can synergistically, and to some extent differentially, activate various RA-responsive promoters (Leid et al., TIBS 17:427-433 (1992); Nagpal, S., et al., Cell 70:1007-1019 (1992); Nagpal, S., et al., EMBO J. 12:2349-2360 (1993)).
RXR Receptors
Unlike the RARs, members of the retinoid X receptor family (RXRxcex1, xcex2 and xcex3) are activated exclusively by 9cis-RA (Chambon, P., FASEB J. 10:940-954 (1996); Chambon, P., Semin. Cell Biol. 5:115-125 (1994); Dollxc3xa9, P., et al., Mech. Dev. 45:91-104 (1994); Linney, E., Current Topics in Dev. Biol. 27:309-350 (1992); Leid et al., TIBS 17:427-433 (1992); Kastner et al., in Vitamin A in Health and Disease, R. Blomhoff, ed., Marcel Dekker, New York (1993)). However, the RXRs characterized to date are similar to the RARs in that the different RXR types also differ markedly in their N-terminal A/B regions (Leid et al., TIBS 17:427433 (1992); Leid et al., Cell 68:377-395 (1992); Mangelsdorf et al., Genes and Dev. 6:329-344 (1992)), and contain the same transcriptional activation functions in their N-terminal A/B region and C-terminal E region (Leid et al., TIBS 17:427-433 (1992); Nagpal, S., et al., Cell 70:1007-1019 (1992); Nagpal, S., et al., EMBO J. 12:2349-2360 (1993)).
RXRxcex1 and RXRxcex2 have a widespread (possibly ubiquitous) expression pattern during mouse development and in the adult animal, being found in all fetal and adult tissues thus far examined (Mangelsdorf, D. J., et al., Genes and Devel. 6:329-344 (1992); Dollxc3xa9, P., et al., Mech. Devel. 45:91-104 (1994); Nagata, T., et al., Gene 142:183-189 (1994)). RXRxcex3 transcripts, however, appear to have a more restricted distribution, being expressed in developing skeletal muscle in the embryo (where their expression persists throughout life), in the heart (after birth), in sensory epithelia of the visual and auditory systems, in specific structures of the central nervous system, and in tissues involved in thyroid hormone homeostasis, e.g, the thyroid gland and thyrotrope cells in the pituitary (Mangelsdorf, D. J., et al., Genes and Devel. 6:329-344 (1992); Dollxc3xa9, P., et al., Mech. Devel. 45:91-104 (1994); Sugawara, A., et al., Endocrinology 136:1766-1774 (1995); Liu, Q., and Linney, E., Mol. Endocrinol. 7:651-658 (1993)).
It is currently unclear whether all the molecular properties of RXRs characterized in vitro are relevant for their physiological functions in vivo. In particular, it is unknown under what conditions these receptors act as 9-cis-RA-dependent transcriptional regulators (Chambon, P., Semin. Cell Biol. 5:115-125 (1994)). The knock-outs of RXRxcex1 and RXRxcex2 in the mouse have provided some insight into the physiological functions of these receptors. For example, the ocular and cardiac malformations observed in RXRxcex1xe2x88x92/xe2x88x92 fetuses (Kastner, P., et al., Cell 78:987-1003 (1994); Sucov, H. M., et al., Genes and Devel. 8:1007-1018 (1994)) are similar to those found in the fetal VAD syndrome, thus suggesting an important function of RXRxcex1 in the transduction of a retinoid signal during development. The involvement of RXRs in retinoid signaling is further supported by studies of compound RXRxcex1/RAR mutants, which reveal defects that are either absent or less severe in the single mutants (Kastner, P., et al., Cell 78:987-1003 (1994); Kastner, P., et al., Cell 83:859-869 (1995)). Interestingly, however, knockout of RXRxcex3 in the mouse induces no overt deleterious effects, and RXRxcex3xe2x88x92/xe2x88x92 homozygotes which are also RXRxcex1xe2x88x92/xe2x88x92 or RXRxcex2xe2x88x92/xe2x88x92 exhibit no additional abnormalities beyond those seen in RXRxcex1xe2x88x92/xe2x88x92, RXRxcex2xe2x88x92/xe2x88x92 and fetal VAD syndrome fetuses (Krezel, W., et al., Proc. Natl. Acad Sci. USA 93(17):9010-9014 (1996)), suggesting that RXRxcex3, despite its highly tissue-specific expression pattern in the developing embryo, is dispensable for embryonic development and postnatal life in the mouse. The observation that live-born RXRxcex3xe2x88x92/xe2x88x92/RXRxcex2xe2x88x92/xe2x88x92/RXRxcex1+/xe2x88x92 mutants can grow to reach adult age (Krezel et al., Proc. Natl. Acad Sci. USA 93(17):9010-9014 (1996)) indicates that a single RXRxcex1 allele is sufficient to carry out all of the vital developmental and postnatal functions of the RXR family of receptors, particularly all of the developmental functions which depend on RARs and may require RXR partnership (Dollxc3xa9, P., et al., Mech. Dev. 45:91-104 (1994); Kastner, P., et al., Cell 83:859-869 (1995)). Furthermore, the finding that RXRxcex1xe2x88x92/xe2x88x92/RXRxcex3xe2x88x92/xe2x88x92 double mutant embryos are not more affected than are single RXRxcex1xe2x88x92/xe2x88x92 mutants (Krezel et al., Proc. Natl. Acad. Sci. USA 93(17):9010-9014 (1996)) clearly shows that RXRxcex2 alone can also perform some of these functions. Therefore, the fact that RXRxcex1 alone and, to a certain extent RXRxcex2 alone, are sufficient for the completion of a number of developmental RXR functions, clearly indicates the existence of a large degree of functional redundancy amongst RXRs. In this respect, the RXR situation is different from that of RARs, since all of types of RAR double mutants displayed much broader sets of defects than single mutants (Rowe, A., et al., Develop. 111:771-778 (1991); Lohnes, D., et al., Develop. 120:2723-2748 (1994); Mendelsohn, C., Devlop. 120:2749-2771 (1994)).
Retinoid Binding to RAR and RXR Receptors
The crystal structures of the ligand-binding domains (LBDs) of the RARs and RXRs have recently been elucidated (Bourget, W., et al., Nature 375:377-382 (1995); Renaud, J. P., et al., Nature 378:681-689 (1995); Wurtz, J. M., et al., Nature Struct. Biol. 3:87-94 (1996)). Among the various RAR types, substantial amino acid sequence identity is observed in these domains: comparison of the LBDs of RARxcex1, RARxcex2 and RARxcex3 indicates that only three amino acid residues are variable in the ligand-binding pocket of these receptors. These residues apparently account for the fact that the various RAR types exhibit some selectivity in binding certain synthetic retinoids (Chen, J.-Y., et al., EMBO J. 14(6): 1187-1197 (1995); Renaud, J. P., et al., Nature 378:681-689 (1995)), and consideration of these divergent residues can be used to design RAR type-specific synthetic retinoids which may be agonistic or antagonistic (Chambon, P., FASEB J. 10:940-954 (1996)). This design approach may be extendable generally to other nuclear receptors, such as thyroid receptor a (Wagner, R. L., et al., Nature 378:690-697 (1995)), the ligand-binding pockets of which may chemically and structurally resemble those of the RARs (Chambon, P., FASEB J. 10:940-954 (1996)). Conversely, molecular modeling of the ligand-binding pocket of the RXRs demonstrates that there are no overt differences in amino acid composition between RXRxcex1, RXRxcex2 and RXRxcex3 (Bourguet, W., et al., Nature 375:377-382 (1995); Wurtz, J. M., et al., Nature Struct. Biol. 3:87-94 (1996)), suggesting that design of type-specific synthetic ligands for the RXRs may be more difficult than for the RARs (Chambon, P., FASEB J. 10:940-954 (1996)).
Retinoid Signaling Through RAR:RXR Heterodimers
Nuclear receptors (NRs) are members of a superfamily of ligand-inducible transcriptional regulatory factors that include receptors for steroid hormones, thyroid hormones, vitamin D3 and retinoids (Leid, M., et al., Trends Biochem. Sci. 17:427-433 (1992); Leid, M., et al., Cell 68:377-395 (1992); and Linney, E. Curr. Top. Dev. Biol., 27:309-350 (1992)). NRs exhibit a modular structure which reflects the existence of several autonomous functional domains. Based on amino acid sequence similarity between the chicken estrogen receptor, the human estrogen and glucocorticoid receptors, and the v-erb-A oncogene (Krust, A., et al., EMBO J. 5:891-897 (1986)), defined six regionsxe2x80x94A, B, C, D, E and Fxe2x80x94which display different degrees of evolutionary conservation amongst various members of the nuclear receptor superfamily. The highly conserved region C contains two zinc fingers and corresponds to the core of the DNA-binding domain (DBD), which is responsible for specific recognition of the cognate response elements. Region E is functionally complex, since in addition to the ligand-binding domain (LBD), it contains a ligand-dependent activation function (AF-2) and a dimerization interface. An autonomous transcriptional activation function (AF-1) is present in the non-conserved N-terminal A/B regions of the steroid receptors. Interestingly, both AF-1and AF-2 of steroid receptors exhibit differential transcriptional activation properties which appear to be both cell type and promoter context specific (Gronemeyer, H. Annu. Rev. Genet 25:89-123 (1991)).
As described above, the all-trans (T-RA) and 9-cis (9C-RA) retinoic acid signals are transduced by two families of nuclear receptors, RAR xcex1, xcex2 and xcex3 (and their isoforms) are activated by both T-RA and 9C-RA, whereas RXR xcex1, xcex2 and xcex3 are exclusively activated by 9C-RA (Allenby, G. et al., Proc. Natl. Acad. Sci. USA 90:30-34 (1993)). The three RAR types differ in their B regions, and their main isoforms (xcex11 and xcex12, xcex21-4, and xcex31 and xcex32) have different N-terminal A regions (Leid, M. et al., Trends Biochem. Sci. 17:427-433 (1992)). Similarly, the RXR types differ in their A/B regions (Mangelsdorf, D. J. et al., Genes Dev. 6:329-344 (1992)).
The E-region of RARs and RXRs has also been shown to contain a dimerization interface (Yu, V. C. et al., Curr. Opin. Biotechnol. 3:597-602 (1992)). Most interestingly, it was demonstrated that RAR/RXR heterodimers bind much more efficiently in vitro than homodimers of either receptor to a number of RA response elements (RAREs) (Yu, V. C. et al., Cell 67:1251-1266 (1991); Berrodin, T. J. et al., Mol. Endocrinol 6:1468-1478 (1992); Bugge, T. H. et al., EMBO J. 11:1409-1418 (1992); Hall, R. K. et al., Mol. Cell. Biol. 12:5527-5535 (1992); Hallenbeck, P. L. et al., Proc. Natl. Acad. Sci. USA 89:5572-5576 (1992); Husmann, M. et al., Biochem. Biophys. Res. Commun. 187:1558-1564 (1992); Kliewer, S. A. et al., Nature 355:446-449 (1992); Leid, M. et al., Cell 68:377-395 (1992); Marks, M. S. et al., EMBO J. 11:1419-1435 (1992); Zhang, X. K. et al., Nature 355:441-446 (1992)). RAR and RXR heterodimers are also preferentially formed in solution in vitro (Yu, V. C. et al., Cell 67:1251-1266 (1991); Leid, M. et al., Cell 68:377-395 (1992); Marks, M. S. et al., EMBO J. 11:1419-1435 (1992)), although the addition of 9C-RA appears to enhance the formation of RXR homodimers in vitro (Lehman, J. M. et al., Science 258:1944-1946 (1992); Zhang, X. K. et al., Nature 358:587-591 (1992b)).
It has been shown that activation of RA-responsive promoters likely occurs through RAR:RXR heterodimers rather than through homodimers (Yu, V. C. et al., Cell 67:1251-1266 (1991); Leid et al., Cell 68:377-395 (1992b); Durand et al., Cell 71:73-85 (1992); Nagpal et al., Cell 70:1007-1019 (1992); Zhang, X. K., et al., Nature 355, 441-446 (1992); Kliewer et al., Nature 355:446-449 (1992); Bugge et al., EMBO J. 11:1409-1418 (1992); Marks et al., EMBO J. 11:1419-1435 (1992); Yu, V. C. et al., Cur. Op. Biotech. 3:597-602 (1992); Leid et al., TIBS 17:427-433 (1992); Laudet and Stehelin, Curr. Biol. 2:293-295 (1992); Green, S., Nature 361:590-591 (1993)). The RXR portion of these heterodimers has been proposed to be silent in retinoid-induced signaling (Kurokawa, R., et al., Nature 371:528-531 (1994); Forman, B. M., et al., Cell 81:541-550 (1995); Mangelsdorf, D. J., and Evans, R. M., Cell 83:835-850 (1995)), although conflicting results have been reported on this issue (Apfel, C. M., et al., J. Biol. Chem. 270(51):30765-30772 (1995); see Chambon, P., FASEB J. 10:940-954 (1996) for review). Although the results of these studies strongly suggest that RAR/RXR heterodimers are indeed functional units that transduce the RA signal in vivo, it is unclear whether all of the suggested heterodimeric combinations occur in vivo (Chambon, P., Semin. Cell Biol. 5:115-125 (1994)). Thus, the basis for the highly pleiotropic effect of retinoids may reside, at least in part, in the control of different subsets of retinoid-responsive promoters by cell-specifically expressed heterodimeric combinations of RAR:RXR types (and isoforms), whose activity may be in turn regulated by cell-specific levels of all-trans- and 9-cis-RA (Leid et al., TIBS 17:427-433 (1992)).
The RXR receptors may also be involved in RA-independent signaling. For example, the observation of aberrant lipid metabolism in the Sertoli cells of RXRxcex2xe2x88x92/xe2x88x92 mutant animals suggests that functional interactions may also occur between RXRxcex2 and the peroxisomal proliferator-activated receptor signaling pathway (WO 94/26100; Kastner, P., et al., Genes and Devel. 10:80-92 (1996)).
Therapeutic Uses of Retinoids
Overview
As retinoic acid is known to regulate the proliferative and differentiative capacities of several mammalian cell types (Gudas, L. J., et al., In The Retinoids, 2nd ed., Sporn, M. B., et al., eds., New York: Raven Press, pp. 443-520 (1994)), retinoids are used in a variety of chemopreventive and chemotherapeutic settings. The prevention of oral, skin and head and neck cancers in patients at risk for these tumors has been reported (Hong, W. K. et al., N. Engl. J. Med. 315:1501-1505 (1986); Hong, W. K. et al., N. Engl. J. Med. 323:795-801 (1990); Kraemer, K. H. et al., N. Engl. J. Med. 318:1633-1637 (1988); Bollag, W. et al., Ann. Oncol. 3:513-526 (1992); Chiesa, F. et al., Eur. J. Cancer B. Oral Oncol. 28:97-102 (1992); Costa, A. et al., Cancer Res. 54:Suppl. 7, 2032-2037 (1994)). Retinoids have also been used to treat squamous cell carcinoma of the cervix and the skin (Verma, A. K., Cancer Res. 47:5097-5101 (1987); Lippman S. M. et al., J. Natl Cancer Inst. 84:235-241 (1992); Lippman S. M. et al., J. Natl Cancer Inst. 84:241-245 (1992)) and Kaposi""s sarcoma (Bonhomme, L. et al., Ann. Oncol. 2:234-235 (1991)), and have found significant use in the therapy of acute promyelocytic leukemia (Huang, M. E. et al., Blood 72:567-572 (1988); Castaigne, S. et al., Blood 76:1704-1709 (1990); Chomienne, C. et al., Blood 76:1710-1717 (1990); Chomienne, C. et al., J. Clin. Invest. 88:2150-2154 (1991); Chen Z. et al., Leukemia 5:288-292 (1991); Lo Coco, F. et al., Blood 77:1657-1659 (1991); Warrell, R. P., et al., N. Engl. J. Med. 324:1385-1393 (1991); Chomienne, C., et al., FASEB J. 10:1025-1030 (1996)).
Acute Promyelocytic Leukemia (APL)
A balanced chromosomal translocation, t(15;17), has been identified in most acute promyelocytic leukemia (APL) cells (Larson, A. R., et al., Am. J. Med. 76:827-841 (1984)). The breakpoint for this translocation occurs within the second intron of the RARxcex1 gene (Alcalay, M. D., et al., Proc. Natl. Acad Sci. USA 88:1977-1981 (1991); Chang, K. S., et al., Leukemia 5:200-204 (1991); Chen, S., et al., Blood 78:2696-2701 (1991) and within two loci of the gene encoding the putative zinc finger transcription factor PML (Goddard, A., et al., Science 254:1371-1374(1991)). This reciprocal t(15;17) translocation leads to the generation of a PML-RARxcex1 fusion protein which is co-expressed with PML and RARxcex1 in APL cells (for reviews and references, see Warrell, R. P., et al., N. Engl. J. Med. 329:177-189 (1993); Grignani, F., et al., Blood 83:10-25 (1994); Lavau, C., and Dejean, A., Leukemia 8:1615-1621 (1994); de Thxc3xa9, H., FASEB J. 10:955-960 (1996)). The PML-RARxcex1 fusion is apparently responsible for the differentiation block at the promyelocytic stage, since (i) it is observed in nearly all APL patients (Warrell, R. P., et al., N. Engl. J. Med. 329:177-189 (1993); Grignxc3xa1ni, F., et at, Blood 83:10-25 (1994); Lavau, C., and Dejean, A., Leukemia 8:1615-1621 (1994)), (ii) it inhibits myeloid differentiation when overexpressed in U937 or HL60 myeloblastic leukemia cells (Grignani, F., et al., Cell 74:423-431 (1993)), and (iii) complete clinical remission due to differentiation of the leukemic cells to mature granulocytes upon treatment with all-trans retinoic acid (T-RA) is tightly linked to PML-RARxcex1 expression (Warrell, R. P., et al., N. Engl. J. Med. 324:1385-1393 (1991); Lo Coco, R., et al., Blood 77:1657-1659 (1991); Chomienne, C., et al., FASEB J. 10:1025-1030 (1996)). Multiple studies have addressed the possible impact of PML-RARxcex1 fusion protein formation on cell proliferation (Mu, X. M., et al., Mol. Cell. Biol. 14:6858-6867 (1994)) and apoptosis (Grignani, F., et al., Cell 74:423-431 (1993)), APP1 transrepression (Doucas, V., et al., Proc. Natl. Acad Sci. USA 90:9345-9349 (1993)), and vitamin D3 signaling (Perez, A., et al., EMBO J. 12:3171-3182 (1993)), but the mechanism(s) by which PML-RARxcex1 blocks myeloid cell maturation has remained elusive. Consistent with the aberrant nuclear compartmentalization of PML-RARxcex1, which adopts the xe2x80x9cPML-typexe2x80x9d location upon RA treatment (Dyck, J. A., et al., Cell 76:333-343 (1994); Weis, K., et al., Cell 76:345-358 (1994); Koken, M. H., et al., EMBO J. 13:1073-1083 (1994)), the currently prevailing hypothesis is that PML-RARxcex1 possesses altered transcriptional properties compared to PML or RARxcex1 and/or may act in a dominant-negative manner (Perez, A., et al., EMBO J. 12:3171-3182 (1993); de Thexc3xa9, H., et al., Cell 66:675-684 (1991); Kastner, P., et al., EMBO J. 11:629-642 (1992)).
By the invention, a method is provided for treating an animal, preferably a human, suffering from or predisposed to a physical disorder. The method comprises administering to the animal an effective amount of a composition comprising at least one RAR antagonist, preferably an RARxcex1 antagonist, and most preferably Compound A or Compound B, and at least one RXR agonist, most preferably SR11237. The combination of an RXR agonist, which has no therapeutic effects alone, with an RAR antagonist allows the use of lower doses of the RAR antagonist than were previously thought to be efficacious; this approach obviates many of the undesirable physiological side-effects of treatment with RAR antagonists. Physical disorders treatable by the method of the present invention include cancers (preferably a skin cancer, an oral cavity cancer, a lung cancer, a mammary gland cancer, a prostatic cancer, a bladder cancer, a liver cancer, a pancreatic cancer, a cervical cancer, an ovarian cancer, a head and neck cancer, a colon cancer, a germ cell cancer such as a teratocarcinoma or a leukemia, and most preferably acute promyelocytic leukemia), a skin disorder (preferably psoriasis, actinic keratosis, acne, ichthyosis, photoaging or corticosteroid-induced skin atrophy), rheumatoid arthritis and a premalignant lesion.
The invention also provides pharmaceutical compositions comprising at least one RAR antagonist which is preferably an RARxcex1 antagonist and most preferably Compound A or Compound B, at least one RXR agonist which is most preferably SR11237, and a pharmaceutically acceptable carrier or excipient therefor. The invention further encompasses the use of these pharmaceutical compositions in treating an animal, preferably a human, that is suffering from or is predisposed to a physical disorder. Physical disorders treatable using the pharmaceutical compositions of the present invention include those described above.
Other preferred embodiments of the present invention will be apparent to one of ordinary skill in light of the following drawings and description of the invention, and of the claims.